Structural Insights Into How Proteoglycans Determine Chemokine-CXCR1/CXCR2 Interactions: Progress and Challenges
Proteoglycans (PGs), present in diverse environments, such as the cell membrane surface, extracellular milieu, and intracellular granules, are fundamental to life. Sulfated glycosaminoglycans (GAGs) are covalently attached to the core protein of proteoglycans. PGs are complex structures, and are div...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2020-04-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.00660/full |
| _version_ | 1818213963308990464 |
|---|---|
| author | Krishna Rajarathnam Krishna Rajarathnam Krishna Rajarathnam Umesh R. Desai |
| author_facet | Krishna Rajarathnam Krishna Rajarathnam Krishna Rajarathnam Umesh R. Desai |
| author_sort | Krishna Rajarathnam |
| collection | DOAJ |
| description | Proteoglycans (PGs), present in diverse environments, such as the cell membrane surface, extracellular milieu, and intracellular granules, are fundamental to life. Sulfated glycosaminoglycans (GAGs) are covalently attached to the core protein of proteoglycans. PGs are complex structures, and are diverse in terms of amino acid sequence, size, shape, and in the nature and number of attached GAG chains, and this diversity is further compounded by the phenomenal diversity in GAG structures. Chemokines play vital roles in human pathophysiology, from combating infection and cancer to leukocyte trafficking, immune surveillance, and neurobiology. Chemokines mediate their function by activating receptors that belong to the GPCR class, and receptor interactions are regulated by how, when, and where chemokines bind GAGs. GAGs fine-tune chemokine function by regulating monomer/dimer levels and chemotactic/haptotactic gradients, which are also coupled to how they are presented to their receptors. Despite their small size and similar structures, chemokines show a range of GAG-binding geometries, affinities, and specificities, indicating that chemokines have evolved to exploit the repertoire of chemical and structural features of GAGs. In this review, we summarize the current status of research on how GAG interactions regulate ELR-chemokine activation of CXCR1 and CXCR2 receptors, and discuss knowledge gaps that must be overcome to establish causal relationships governing the impact of GAG interactions on chemokine function in human health and disease. |
| first_indexed | 2024-12-12T06:12:38Z |
| format | Article |
| id | doaj.art-35e3452943094604968abacf81b607cb |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T06:12:38Z |
| publishDate | 2020-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-35e3452943094604968abacf81b607cb2022-12-22T00:35:08ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-04-011110.3389/fimmu.2020.00660527831Structural Insights Into How Proteoglycans Determine Chemokine-CXCR1/CXCR2 Interactions: Progress and ChallengesKrishna Rajarathnam0Krishna Rajarathnam1Krishna Rajarathnam2Umesh R. Desai3Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch at Galveston, Galveston, TX, United StatesSealy Center for Structural Biology and Molecular Biophysics, The University of Texas Medical Branch at Galveston, Galveston, TX, United StatesDepartment of Microbiology and Immunology, The University of Texas Medical Branch at Galveston, Galveston, TX, United StatesDepartment of Medicinal Chemistry, Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, United StatesProteoglycans (PGs), present in diverse environments, such as the cell membrane surface, extracellular milieu, and intracellular granules, are fundamental to life. Sulfated glycosaminoglycans (GAGs) are covalently attached to the core protein of proteoglycans. PGs are complex structures, and are diverse in terms of amino acid sequence, size, shape, and in the nature and number of attached GAG chains, and this diversity is further compounded by the phenomenal diversity in GAG structures. Chemokines play vital roles in human pathophysiology, from combating infection and cancer to leukocyte trafficking, immune surveillance, and neurobiology. Chemokines mediate their function by activating receptors that belong to the GPCR class, and receptor interactions are regulated by how, when, and where chemokines bind GAGs. GAGs fine-tune chemokine function by regulating monomer/dimer levels and chemotactic/haptotactic gradients, which are also coupled to how they are presented to their receptors. Despite their small size and similar structures, chemokines show a range of GAG-binding geometries, affinities, and specificities, indicating that chemokines have evolved to exploit the repertoire of chemical and structural features of GAGs. In this review, we summarize the current status of research on how GAG interactions regulate ELR-chemokine activation of CXCR1 and CXCR2 receptors, and discuss knowledge gaps that must be overcome to establish causal relationships governing the impact of GAG interactions on chemokine function in human health and disease.https://www.frontiersin.org/article/10.3389/fimmu.2020.00660/fullglycosaminoglycanproteoglycanchemokinenuclear magnetic resonancestructureheparan sulfate |
| spellingShingle | Krishna Rajarathnam Krishna Rajarathnam Krishna Rajarathnam Umesh R. Desai Structural Insights Into How Proteoglycans Determine Chemokine-CXCR1/CXCR2 Interactions: Progress and Challenges Frontiers in Immunology glycosaminoglycan proteoglycan chemokine nuclear magnetic resonance structure heparan sulfate |
| title | Structural Insights Into How Proteoglycans Determine Chemokine-CXCR1/CXCR2 Interactions: Progress and Challenges |
| title_full | Structural Insights Into How Proteoglycans Determine Chemokine-CXCR1/CXCR2 Interactions: Progress and Challenges |
| title_fullStr | Structural Insights Into How Proteoglycans Determine Chemokine-CXCR1/CXCR2 Interactions: Progress and Challenges |
| title_full_unstemmed | Structural Insights Into How Proteoglycans Determine Chemokine-CXCR1/CXCR2 Interactions: Progress and Challenges |
| title_short | Structural Insights Into How Proteoglycans Determine Chemokine-CXCR1/CXCR2 Interactions: Progress and Challenges |
| title_sort | structural insights into how proteoglycans determine chemokine cxcr1 cxcr2 interactions progress and challenges |
| topic | glycosaminoglycan proteoglycan chemokine nuclear magnetic resonance structure heparan sulfate |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.00660/full |
| work_keys_str_mv | AT krishnarajarathnam structuralinsightsintohowproteoglycansdeterminechemokinecxcr1cxcr2interactionsprogressandchallenges AT krishnarajarathnam structuralinsightsintohowproteoglycansdeterminechemokinecxcr1cxcr2interactionsprogressandchallenges AT krishnarajarathnam structuralinsightsintohowproteoglycansdeterminechemokinecxcr1cxcr2interactionsprogressandchallenges AT umeshrdesai structuralinsightsintohowproteoglycansdeterminechemokinecxcr1cxcr2interactionsprogressandchallenges |